Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice.

SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone ß-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.

Changes of ubiquitin C-terminal hydrolase-L1 levels in serum and urine of patients with white matter lesions.

OBJECTIVES: Ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) has been established as a potential biomarker of neuronal damage. There is not much information about the effects of white matter lesions (WMLs) on serum and urine UCH-L1 levels in white matter disease patients. This study was aimed to assess whether serum or urine UCH-L1 levels are a reliable marker of brain damage in patients with WMLs. DESIGN AND METHODS: Serum and urine levels of UCH-L1 were assessed in 125 patients with dizziness, hypertension, type 2 diabetes mellitus, or dyslipidemia. Of these 125 patient cases, 41 showed periventricular WMLs (P-WMLs), 46 showed subcortical WMLs (S-WMLs), and 38 displayed no well-defined WMLs (controls). RESULTS: Serum UCH-L1 levels were significantly different between the WML group and controls (p<0.05). Further subgroup analysis proved that serum UCH-L1 levels in participants with S-WMLs were significantly increased when compared with controls (p<0.001), but there was no significant differences between controls and patients with P-WMLs (p>0.05). However, urine levels of UCH-L1 were similar between these three groups (p>0.05). In addition, multivariate analysis showed that increased serum UCH-L1 levels were independently associated with the severity of WMLs using Fazekas scale (ß=0.432, p<0.001). CONCLUSIONS: These findings suggest that serum UCH-L1 levels may serve as a novel biomarker for neuronal damage from WMLs, especially S-WMLs.